Method for the preparation of diaryl ketones



United States Patent ()fifice 3,031,506 Patented Apr. 24,1962

3,031,506 METHBD FGR THE PREPARATION F DIARYL KETQNES Reynold C. Fuson, Urhana, Ill., and Bruno M. Vittimberga, Philadelphia, Pa, assignors to Rohrn & Haas Company, Philadelphia, Pa, a corporation of Delaware N0 Drawing, Filed July 29, 1958, Ser. No. 751,615

8 Claims. (ill. 260-591) This invention dealswith a method for the preparation of specific diaryl ketones.

The present invention deals with a reaction between a specific aromatic compound and a specific 2,6-disubstituted benzoic acid in a manner to be more fully described hereinafter. The 2,6-disubstituted beuzoic acid reactants of this invention may be represented by the formula I R R1 R coon I l-l R2 R and R indiivdually represent alkyl groups of one to three carbon atoms in which the three-carbon representation is the iso structure and these may be methyl, ethyl, and isopropyl groups. R and R preferably represent the same alkyl group in any one compound but they may stand for different alkyl representations within the definition just given. R R and R may represent the same or difierent components and these individually include a hydrogen atom, an alkyl group of one to two carbon atoms, i.e. methyl or ethyl, an n-alkoxyl group of one to twenty-one carbon atoms, a phenoxyl group, or a phenoxyl group substituted with one to five groups preferably ortho and para directing groups. Typically, in addition to the alkyl representations previously presented, R R

and R may be methoxyl, propoxyl, butoxyl, octoxyl, decoxyl, dodecoxyl, tetradecoxyl, octadecoxyl, eicosoxyl, heneicosoxyl, phenoxyl, p-chlorophenoxyl, p-methoxyphenoxyl, m-nitrophenoxyl, p-methylphenoxyl, and the like.

In addition, when R and R represent hydrogen atoms, then R can also represent alkyl groups of three to twelve carbon atoms in any of the known structural configurations but preferably branch chained, such as isopropyl, tert-butyl, hexyl, octyl, nonyl, tert-decyl, undecyl, and tert-dodecyl. Furthermore, it is possible for R and R collectively or R and R collectively to represent a bridge having the formula in which n is an integer of one to ten, preferably one to two. In addition, R and R collectively or R and R collectively, or both, may represent bridges containing from three to thirteen carbon atoms. When R and R as well as R and R both represent bridges, then there is the requirement that the total number of carbon atoms in the two bridges must be at least seven. The term, bridges, in the above sense, is used to include both the carbon atoms in a direct chain and also these chains with alkyl substituents as will be apparent to one skilled in the art. While is is preferable and usual that these bridges be entirely hydrocarbon in nature, it is quite permissible that they contain hetero atoms, such as oxygen, sulfur, and nitrogen. These hetero atoms will be present in ether, thioether, amino, or substituted amino groups with the restriction that these hetero atoms must not be in the ortho position with respect to the carboxyl group and also that there be at least two carbon atoms between each of the hetero atoms present. There may be present as many hetero atoms in these bridges as is possible within the above definition and restriction, but generally only one or two hetero atoms will be present in any single bridge. If an amino nitrogen atom is present in the aforementioned bridges, its remaining valence may be satisfied by either a hydrogen atom or an alkyl group of one to twenty-one carbon atoms, such as methyl, ethyl, butyl, octyl, dodecyl, octadecyl, .and eicosyl. It will generally be preferable to have these bridges hydrocarbon in nature, such as tetramethylene, hexamethylene, octamethylene, dodecamethylene or tridecamethylene, and when one bridge is tetramethylene, the other may be trimethylene, as indicated hereto-fore. The bridges may also contain alkyl substituents within the number of carbon atoms mentioned heretofore, such as 1,1,4,4-tetramethyltetramethylene, l-methyltrimethylene, and the like.

Typical representations of the 2,6-disubstituted benzoic acid reactants include 2,6-dimethylbenzoic acid, 2-ethyl-6-methylbenzoic acid, 2,3,5,6-tetramethylbenzoic acid, 3-ethyl-2,5,6-trimethylbenzoic acid, 2,3,4,5,6-pentamethylbenzoic acid, 4-e-thyl-2,3,5,6-tetramethylbenzoic. acid, 4-bro-mo-2,3,5,6-tetramethylbenzoic acid, 4-methoXy-2,3,5,6-tetramethylbenzoic acid, 4-phenoxy-2,3,5,6-tetramethylbenzoic acid, 4-isopropyl-2,6-dimethylbenzoic acid, 4-tert-butyl-2,G-dimethylbenzoic acid, 4-( a,a-dimethyl) decyl-2,6-dimethylbenzoic acid, 2,6-dimethyl-3,4-rnethylenedioxybenzoic acid, 2,6-dimethyl-3,4-hexamethylenedioxybenzoic acid, 1,2,3,4,5,6,7,8-octahydroantbracene-9carboxylic acid, 2,3heXamethylene-5,6hexamethylenebenzoic acid, 1,2,3,4,5,6,7,8-octahydro-2-azaanthracene-9-carboxylic acid, 1,2,3,4,5,6,7,8-octahydro-2-methyl-2azaanthracene-9- carboxylic acid, 3 ,4,5,6,7 ,8-hexahydro-2 1H] oxaanthracene-S -carboxylic acid, 1,2,3,4,5,6,7,8-octahydro-2,7-diazaanthracene-9- carboxylic acid, 1,2,3,4,5,6,7,8-octahydro-2,7-dimethyl-2,7-diazaanthracene-Q-carboxylic acid, 1,2,3,4,5,6,7,8-octahydro-l-azaanthracene-IO- carboxylic acid, 2,3,4,5,6,7,8-heptahydro-l-oxaanthracene-IO- carboxylic acid, 1,3,4,5,7,8,9,10-octahydro-naphth[2,3-c] [2,S]oxaazepine-ll-carboxylic acid, 2,3,4,5,6,7,8-heptahydro-l-thiaanthracene-IO- carboxylic acid, 1,3,4,5,6,7,8-heptahydro-2-oxa-7-azaanthracene-9= carboxylic acid, 2,3,4,5,6,7,8-heptahydro-1-oxa-6-azaanthracene-l0- carboxylic acid, 5,6,7,8-tetrahydrobenz[f]isoindoline-9-carboxylic acid, 1,3,5,6,7,8-hexahydrobenz[f]isothianaphthene-9.

carboxylic acid, 1 2,7r-dimethylal,2,3,4,5,6,7,8-octahydroanthracene-9- carboxylic acid, and Z-methyl-1,2,3,4,5,6,7,8-octahydroanthracene-9- carboxylic acid.

The other reactant employed in the present process, the

The symbols W, X, Y, and Z may represent hydrogen atoms or alkyl groups of one to three carbon atoms, in which the three-carbon atom member is iso in structure, in any possible combination of hydrogen atoms and defined alkyl groups. If only two, or three of these symbols represent hydrogen atoms,'then the remaining two or one may represent alkyl groups of up to twelve carbon atoms including all of the known configurations, such as normal, iso, and tertiary. It is also possible to have one or two chlorine or bromine atoms present provided they are the only substituents. It is further possible to have one or two n-alkoxyl substituents in which the alkyl portion contains from one to twenty-one carbon atoms or one to two phenoxyl or phenoxyl groups substituted with from one to five groups, preferably orthoand para-directing groups Typical representations of W, X, Y, and Z, according to the above definition, in addition to the methyl, ethyl and isopropyl groups referred to heretofore include butyl, pentyl, hexyl, nonyl, decyl, and dodecylin any of the known spatial configurations, methoxyl, ethoxyl, propoxyl, heptoxyl, octoxyl, dodecoxyl, octadecoxyl, eicosoxyl, phenoxyl, p-chlorophenoxyl, p-methoxyphenoxyl, m-nitrophenoxyl, p-methylphenoxyl, and the like.

Typical representations of the aromatic reactant just defined include benzene, 1,2,3,4-tetramethylbenzene, mxylene, o-xylene, 1,2,3-trimethylbenzene, 1,3,4-trimethylbenzene, toluene, anisole, 1,2-dimethoxybenzene, octadecyl phenyl ether, 2,4-di-tert-butylbenzene, l-methyl-3- tert-dodecylbenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1-bromo-3-chlorobenzene, chlorobenzene, bromobenzene, and diphenyl ether.

The present reaction is conducted in the temperature range of about 25 to 235 C., preferably 50" to 200 C., with the restriction that a temperature must be employed in this range at which the carboxyl-bearing reactant is freed of its carboxyl group. This temperature may be determined by the fact that the carboxyl-bearing reactant, once freed of its carboxyl group, is generally isolable or removable from the reaction medium by known methods and frequently may be recognized by its volatility or sublimity. The reaction is conducted until the carboxyl group is substantially completely removed from the carboxyl-bearing reactant at which time the reaction is consummated and highest yields are obtained. One skilled in the art will be able to determine readily the necessary temperature within the defined range from the teachings of this invention.

It is preferred to use an excess of the aromatic hydrocarbon reactant. It is necessary for the successful consummation of the reaction to react two equivalents of the aromatic hydrocarbon reactant with one of the carboxylcontaining reactants, and it is preferred to employ an excess of the aromatic hydrocarbon reactant beyond that necessary to combine with the carboxyl-containing reactant in order to induce maximum yields of the desired product.

It is possible to employ an equivalent of two different aromatic hydrocarbon reactants with an equivalent of the carboxyl-bearing reactant to form a mixture of three products, two symmetrical. and one unsymmetrical, as will be apparent to one skilled in the art. It is preferred to employ two equivalents of a single aromatic hydrocarbon reactant in order to minimize problems of separation of product. The reaction is generally conducted at atmospheric pressures but reduced pressures may be employed, if desired, as would be apparent to one skilled in the art in applying the teachings of this invention.

The present reaction requires a narrowly defined catalyst, including phosphorous pentoxide, at least essentially 85% phosphoric acid, combinations of phosphorous pentoxide and the defined phosphoric acid, particularly those combinations known as polyphosphoric acid, and Lewis acids such as zinc chloride, ferric chloride, mercuric chloride, stannic chloride, aluminum chloride, boron trifluoride,.and boron trifluoride etherates and complexes.

It is important to note here that aluminum chloride should be employed at the milder temperatures within the defined range or otherwise it sometimes causes undesired isomerizations. The preferred catalyst is phosphorous pentoxide, phosphoric acid and combinations thereof particularly those known as polyphosphoric acid in that higher yields and shorter reaction times are consistently observed with this catalyst. The above agents may be defined in the present circumstances as carboxylremoving catalysts.

A solvent of the volatile, but relatively high boiling, inert organic type, may be desirable in some instances, particularly if the catalyst and reactants are solids. However, if the catalyst, such as polyphosphoric acid, is liquid or at least one of the reactants is liquid, then the reaction proceeds favorably without a solvent. It is frequently possible, when the aromatic hydrocarbon reactant of Formula II, referred to hereinbefore, is a liquid, to employ an extra amount of said reactant to function as a solvent as well. sary or desirable, there may be employed'saturated aliphatic hydrocarbons, such as hexane, decahydronaphthalene, and the like, or high molecular weight aliphatic others, such as dipentyl ether, dihexyl ether, and the like. These may be removed at the conclusion of the reaction as desired by known methods such as by distillation under reduced pressure.

At the conclusion of the reaction, the diaryl ketone product, which may be represented by the formula X X if V Y O Y products have known utilities as insecticides and fungicides.

The present process may be more fully understood from the following examples which are offered by way of illustration and not by way of limitation. Parts by Weight are used throughout.

EXAMPLE 1 Preparation of Di-p-Anz'syl Ketone Into a 200 ml. three-necked, ground-glass flask, fitted with a condenser, stirrer, and stopper, is poured 35 parts of warm polyphosphoric acid. To this is added 2 parts of coarsely ground duroic acid and 35 parts of anisole. The mixture is stirred rapidly while the temperature is raised, by means of a sand bath, to C. over a period of one hour. The temperature is held at 80 C. for four hours. The system is opened, and the temperature raised to 160 C. Where it is maintained for seven hours. The hot reaction mixture is then poured into parts of distilled water, and the flask is rinsed with water. The waterorganic mixture is extracted four times with ether. This ether solution is washed three times with aqueous 5% sodium bicarbonate, and twice with distilled water; it is then dried over anhydrous sodium sulfate. 7

The filtered ether solution is concentrated under water aspirator vacuum and dried under high vacuum for five minutes, giving orange crystals. One crystallization from ethanol yields 1.35 parts of organe-tinted plates, M.P. 143 C. (Literature value for di-p-anisyl ketone, 143-144 C.). The yield is 50% of the theoretical amount. By concentration of the mother liquor it is pos- When a solvent is deemed neces- Preparation of 4,4'-Di-(p-Phenoxybenzoyl)Diphenyl Ether temperature is held there for four hours. Then the temperature is raised to 160 C. and maintained at this point for seven hours while the excess diphenyl ether is removed under vacuum. The hot reaction mixture is then poured into 100 parts of distilled water and the flask is rinsed with water. The water-organic mixture is extracted with ether. The ether solution is washed several times with aqueous sodium bicarbonate, twice with distilled water and then is dried over anhydrous sodium sulfate.

The drying agent is removed by filtration and the solvent by evaporation at reduced pressure at a temperature of 35 C. The product, 4,4-di-(p-phenoxybenzoyl)diphenyl ether, is purified by chromatography on alumina.

In a similar way, there is produced a ketone product of this invention by reacting 4methoxy-2,3,5,6-tetramethylbenzoic acid with diphenyl ether, using zinc chloride as the catalyst.

EXAMPLE 3 Preparation of 4,4-Dichlorobenz0phenone Polyphosphoric acid (35 parts) is placed in a threenecked flask fitted with a condenser, mechanical stirrer and glass stopper. To this is added, with vigorous stirring, 35 parts of chlorobenzene and 3 parts of 1,2,3,4,5,6,7,8- octahydroanthracene-9-carboxylic acid. The temperature is increased to 160 C. within a period of two hours, using a sand bath to efiect heating, and held at this temperature for one-half hour longer. The system is then opened and the temperature raised to 170 C. within a period of onehalf hour and maintained at this temperature for four hours longer. The work-up of the reaction mixture is carried out in the same manner as in Example 1. The product, 4,4'-dichlorobenzophenone, is purified by recrystallization from ethanol.

'In an analogous manner, there is prepared a ketone of this invention by reacting 1,3,4,5,7,8,9,10-octahydronaph-[2,3-c][2,5]oxaazepine-1l-carboxylic acid with 1- bromo-3-chlorobenzene, using 85% phosphoric acid as the catalyst.

EXAMPLE 4 Preparation of 2,4,2',4-Tetra-Tert-Butylbenz0phenone Polyphosphoric acid (40 parts) is placed in a threenecked flask fitted with reflux condenser, mechanical stirrer, and glass stopper. To this is added 2 parts of 2,3,4,5,6,7,8 heptahydro-l-thiaanthracene--carboxylic acid and 10 parts of 2,4-di-tert-butylbenzene. The stirrer is started and the temperature of the mixture is raised to 80 C. over a period of one hour and held there for four hours. The system is opened and the temperature raised to 160 C. where it is maintained for four hours longer.

The hot reaction mixture is then poured into 100 parts of distilled water and the flask rinsed with water. The water-organic mixture is extracted twice with ether and twice with chloroform. The extracts are combined, washed with aqueous 5% sodium bicarbonate and twice with distilled water. The solution is then dried over anhydrous sodium sulfate. The product, 2,4,2',4'-tetra-tert- 6 butylbenzophenone, is isolated in a manner similar to that employed in Example 1.

In a similar manner, employing m-xylene and duroic acid there is produced 2,4,2',4-tetramethylbenzophenone, an orange-red oil having a value 11 1.5853.

EXAMPLE 5 Preparation of 2,3,4,5,2',3',4,5-0ctamethylbenzophenone Into a 200 ml. three-necked flask fitted with a condene ser, mechanical stirrer, and glass stopper is placed 35 parts of warm polyphosphoric acid. Then 3 parts of 2,6-dimethyl-3,4-methylenedioxybenzoic acid is added with 35 parts of 1,2,3,4-tetramethylbenzene. The mixture is stirred and the temperature is raised to C. over a period of one hour, by means of a sand bath, and held at this level for four hours. The temperature is then raised to C. where it is maintained for four hours longer. The excess 1,2,3,4-tetramethylbenzene is removed at this temperature under vacuum. The reaction mixture is treated in the manner described in Example 1. The product, 2,3,4,5,2,3',4',5'-octarnethylbenzophenone, is purified by recrystallization from ethanol.

There is similarly produced a ketone of this invention by reacting benzene with 2,6-dimethyl-3,4-hexamethylenedioxy-benzoic acid, using ferric chloride as the catalyst.

EXAMPLE 6 Preparation of 2,2'-Dimethyl-4,4'-Di-Tert I Dodecylbenzophenone In a 200 m1. three-necked flask fitted with a condenser, stirrer, and glass stopper is placed 40 parts of polyphosphoric acid, 2 parts of 1-methyl-3-tert-dodecylbenzene and 10 parts of 1,2,3,4,5,6,7,8-octahydro-2-azaanthracene-9-carboxylic acid. The mixture is stirred rapidly while the temperature is raised to 80 C. over the period of one hour and held there for four hours. The temperature is then raised to 160 C. where it is maintained for four hours. The hot reaction mixture is then treated as described in Example 1. The product, 2,2'-dimethyl- 4,4'-di-tert-dodecylbenzophenone, is purified by recrystallization from chloroform-ethanol.

In an analogous way, there is produced a ketone of this invention by reacting 2,7-dimethyl-1,2,3,4,5,6,7,8- octahydroanthracene-9-carboxylic acid with 1,2,3-trimethylbenzene, using boron trifluoride etherate as the catalyst.

We claim: 1. A method for the preparation of a diaryl ketone having the formula X X t? Y Y N Z which comprises reacting substantially two equivalents of a compound having the formula acid, polyphosphoric acid, zinc chloride, ferric chloride,

mercuric chloride, stannic chloride, aluminum chloride, boron trifluoride, and boron trifluoride etherates, in which W, X, Y, and Z are members from the class consisting of hydrogen, methyl, ethyl, isopropyl, tert-alkyl groups of four to twelve carbon atoms, chlorine, bromine, n alkoxyl groups of one to twenty-one carbon atoms, phenoxyl, chlorophenoxyl, methoxyphenoxyl, nitrophenoxyl, and methylphenoxyl, such that said n-alkoxyl, phenoxyl, substituted phenoxyl, chlorine, and bromine representations are possible only when two to three of said W, X, Y, and Z represent hydrogen, R and R individually represent members from the class consisting of methyl, ethyl, and isopropyl groups, R R and R individually represent members from the class consisting of a hydrogen atom, an alkyl. group of one to two carbon atoms, an n-alkoxyl group of one to twenty-one carbon atoms, phenoxyl, chlorophenoxyl, methoxyphenoxyl, nitrophenoxyl, and methylphenoxyl, When R and R represent hydrogen atoms R additionally represents an alkyl group of three to twelve carbon atoms, R and R when considered collectively represent an oxygenated bridge having the formula O-(CI-I O- in which n is an integer of 1 to and R and R when considered collectively represent an oxygenated bridge having the formula in which n is an integer of one to ten, and at least one of R and R when considered collectively and R and R when considered collectively represent alkylene bridges containing from three to thirteen carbon atoms provided that when R and R considered collectively, and R and R considered collectively, both represent said alkylene bridges, the total number of carbon atoms in the two said alkylene bridges must be at least 7 and in which these bridges contain from zero to two atoms from the class consisting of ether oxygen, thioether sulfur, and amino nitrogen provided that there be at least two carbon atoms between any two atoms of said oxygen, sulfur and nitrogen.

2. A process according to claim 1 in which the reaction temperature range is about 50 to 200 C. and in which the reaction is conducted in the presence of an inert volatile organic solvent, and the catalyst is polyphosphoric acid.

3. A method for the preparation of a diaryl ketone having the formula X x i O Y z z which comprises reacting substantially two equivalents of a compound having the formula in the temperature range of about 25 to 235 C. in the presence of polyphosphoric acid in which R and R are alkyl groups of one to three carbon atoms and W, X, Y, and Z represent alkyl groups of one to three carbon atoms.

8 4. A method for the preparation'of a diaryl ketone with one equivalent of a compound having the formula mooon in the temperature range of about 25 to 235 C. in the presence of polyphosphoric acid in which R and R are alkyl groups of one to three carbon atoms, R is a tertalkyl group of four to twelve carbon atoms, and W, X, Y, and Z represent alkyl groups of one to three carbon atoms.

5. A method for the preparation of a diaryl ketone having the formula which comprises reacting substantially two equivalents of a compound having the formula with one equivalent of a compound having the formula 0 COOH in the temperature range of about 25 to 235 C. in the presence of polyphosphoric acid in which R and R are alkyl groups of one to three carbon atoms, n is an integer of one to ten, and W, X, Y, and Z represent alkyl groups of one to three carbon atoms.

6. A method for the preparation of a diaryl ketone having the formula which comprises reacting substantially two equivalents of a compound having the formula with one equivalent of a compound having the formula X X If Y Y which comprises reacting substantially two equivalents of a compound having the formula with one equivalent of a compound having the formula Hnn COOH (C ahn in the temperature range of about 50 to 200 C. in the presence of polyphosphoric acid in which n and mare integers of tour to thirteen and W, X, Y, and Z represent alkyl groups of one to three carbon atoms.

8. A method for the preparation of a diaryl ketone having the formula X X t Y O Y z z 10 which comprises reacting substantially two equivalents of a compound having the formula with one equivalent of a compound having the formula OOOH R4 R2 in the temperature range of about 50 to 200 C. in the presence of polyphosphoric acid in which R and R are alkyl groups of one to three carbon atoms, R and R are alkyl groups of one to two carbon atoms, and W, X, Y, and Z represent alkyl groups of one to three carbon atoms.

References Cited in the file of this patent UNITED STATES PATENTS 1,866,717 Meyer et a1 July 12, 1932 OTHER REFERENCES Thomas: Anhyd. Aluminum Chloride in Org. Chem. pp. 6834 1941).

Snyder et al.: I. Am. Chem. Soc, vol. 77, pp. 364-5 1955 

1. A METHOD FOR THE PREPARATION OF A DIARYL KETONE HAVING THE FORMULA 